DOI: 10.1183/09031936.00022912
CopyrightERS 2012
AFFILIATIONS
For a full list of affiliations details
please see the Acknowledgements
section.
CORRESPONDENCE
G.B. Migliori
World Health Organization
Collaborating Centre for Tuberculosis
and Lung Diseases
Fondazione S. Maugeri
Care and Research Institute
Via Roncaccio 16
21049
Tradate
Italy
E-mail: giovannibattista.migliori@
fsm.it
Received:
Feb 07 2012
Accepted after revision:
March 19 2012
First published online:
April 10 2012
uberculosis (TB) is a leading cause of morbidity and death worldwide. In the past
decades cases of drug-resistant TB, particularly multidrug-resistant tuberculosis (MDR-TB;
defined as in vitro resistance to at least isoniazid
and rifampicin, the two most potent first-line drugs
for TB treatment) and extensively drug-resistant TB
(XDR-TB; defined as in vitro resistance to isoniazid
and rifampicin plus any fluoroquinolone and at least
one of the second-line injectable drugs: amikacin,
capreomycin or kanamycin), have been described in
almost all countries that have been surveyed [13].
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G. SOTGIU ET AL.
TUBERCULOSIS
Study selection
We included studies that reported complete information
on safety, tolerability and efficacy of linezolid in treating
VOLUME 40 NUMBER 6
1431
G. SOTGIU ET AL.
Statistical analysis
Descriptive, both qualitative and quantitative, variables were
summarised with proportions, medians and interquartile
ranges (IQR); they were compared using the Chi-squared test
and the Wilcoxon MannWhitney test, respectively.
Meta-analytic computations were performed using individual
data taken from patients with a definite treatment outcome
(cure, treatment completion, death, or treatment failure) [41].
Random-effects models were used to account for the predicted
between-study dispersion. Forest plots were used to graphically evaluate both the variability (i.e. 95% CI) of the point
estimates for the efficacy/safety-related covariates and the
weight of every cohort size in the computation of the pooled
estimates. Inconsistency among included studies was assessed
by the Chi-squared test for heterogeneity; the inconsistency (I2)
statistic assesses the role of true variability rather than
sampling error on the overall variation.
Subgroup analyses focused on the safety, efficacy and tolerability of linezolid and were performed between patients treated
with a daily regimen of f600 mg linezolid versus those treated
with a daily regimen of .600 mg linezolid. p-values ,0.05 were
regarded as statistically significant. Statistical analyses were
performed with the Stata 9.0 (StataCorp LP, College Station, TX,
USA) and Meta-Disc Version 1.4 [43] software.
RESULTS
Selection of the studies
The scientific literature search identified 88 citations. 12 clinical
studies were selected, as summarised in the PRISMA flowchart
(fig. 1). The characteristics of the studies and the number of
cases analysed in the systematic review and meta-analysis are
summarised in table 1. The senior and/or correspondence
author of 10 (83.3%) out of 12 studies [8, 3035, 4447]
responded to the electronic invitation to provide demographic,
epidemiological and clinical information missing in the full
texts of the retrieved manuscripts.
Characteristics of the selected studies
Six (50%) out of the 12 studies [8, 22, 33, 35, 44, 47] were
conducted in Europe, four (33.3%) out of the 12 in Asia [31, 32, 45,
46], and two (16.7%) out of the 12 in the USA [30, 34] (table 2).
Eight (66.7%) out of 12 were retrospective observational studies
[8, 22, 30, 3435, 4446] while four (33.3%) out of 12 were
prospective [3133, 47]. The majority (66.7%, eight out of 12) of
the studies were performed in single, university or tertiary, in/
outpatient settings [22, 3132, 35, 4447].
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VOLUME 40 NUMBER 6
Screening
Additional records
identified through other
sources (n=3)
Eligibility
Records identified
through database
search (n=85)
Included
Identification
TUBERCULOSIS
Records screened
(n=88)
Records excluded
(n=66)
Full-text articles
assessed for eligibility
(n=22)
Studies included in
qualitative synthesis
(n=12)
Studies included in
quantitative synthesis,
meta-analysis (n=12)
FIGURE 1.
G. SOTGIU ET AL.
TABLE 1
TUBERCULOSIS
Systematic review
Meta-analysis
treatment outcome:
treatment outcome:
definite#, still on
definite# only
treatment, default,
transferred out
ALFFENAAR [47]
ANGER [34]
16
15
DE LORENZO [35]
12
FORTUN [22]"
NAM [46]
11
11
MIGLIORI [8]+
44
PARK [45]
SCHECTER [30]
30
23
SINGLA [31]
29
14
UDWADIA [32]
18
13
VILLAR [33]
16
10
10
207
121
VON DER
LIPPE [44]"
"
TABLE 2
ALFFENAAR [47]
Country
Study design
Clinical setting
Study duration yr
The Netherlands
Open-label, prospective,
20072008
pharmacokinetic
ANGER [34]
USA
Retrospective
20002006
DE LORENZO [35]
Italy
Retrospective
20092010
Spain
Retrospective
19992004
South Korea
Retrospective
20042007
Retrospective, controlled,
20012007
Switzerland
nonrandomised, unblinded
reference centres
South Korea
Retrospective
20032006
USA
Retrospective
20032007
20062011
FORTUN [22]
NAM [46]
MIGLIORI [8]
PARK [45]
SCHECTER [30]
SINGLA [31]
India
Prospective
UDWADIA [32]
India
Prospective, nonrandomised
20002007
Portugal
Prospective
20042009
Norway
Retrospective
19982002
VILLAR [33]
VON DER
LIPPE [44]
VOLUME 40 NUMBER 6
c
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TUBERCULOSIS
TABLE 3
G. SOTGIU ET AL.
Characteristics of the patients and of the anti-tuberculosis (TB) treatment in the selected studies
Linezolid dosage mg
Control group
No
treatment
ALFFENAAR [47]
No
Individualised
Individualised
No
No
Individualised
No
No
Individualised
No
No
Individualised
No
No
Individualised
Yes
No
Individualised
No
SCHECTER [30]
No
Individualised
No
No
Individualised
No
Individualised
No
Individualised
No
No
Individualised
LIPPE [44]
TABLE 4
No
Demographic, epidemiological and clinical characteristics of 121 multidrug-resistant tuberculosis (TB) cases enrolled
in the meta-analysis
LNZ daily dose f600 mg
65/121 (53.7)
40/72 (55.6)
25/49 (51.0)
0.62
32 (2541)
30.5 (22.541)
33 (2742)
0.42
Total
Male
Age at admission yrs
p-value
Country of birth
Europe
12/75 (16.0)
2/45 (4.4)
10/30 (33.3)
0.0008
Asia
52/75 (69.3)
37/45 (82.2)
15/30 (50.0)
0.003
Africa
6/75 (8.0)
3/45 (6.7)
3/30 (10.0)
0.61
5/75 (6.7)
3/45 (6.7)
2/30 (6.7)
Migrant
29/82 (35.4)
9/45 (20.0)
20/37 (54.1)
0.001
HIV positive
9/104 (8.7)
0/55 (0.0)
9/49 (18.4)
0.0009
93/121 (76.9)
51/72 (70.8)
42/49 (85.7)
0.06
1 (04)
1 (04)
1 (03)
0.81
Sputum-smear positive
102/110 (92.7)
66/72 (91.7)
36/38 (94.7)
0.56
Pulmonary TB
116/120 (96.7)
71/72 (98.6)
45/48 (93.8)
0.15
12/95 (12.6)
4/53 (7.6)
8/42 (19.1)
0.09
Cavitary lesions
39/106 (36.8)
21/69 (30.4)
18/37 (48.7)
0.06
40/106 (37.7)
26/69 (37.7)
14/37 (37.8)
0.99
6/106 (5.7)
5/69 (7.3)
1/37 (2.7)
0.33
Extra-pulmonary TB
Radiological findings
21/106 (19.8)
17/69 (24.6)
4/37 (10.8)
0.09
XDR-TB
39/120 (32.5)
25/71 (35.2)
14/49 (28.6)
0.45
Surgical treatment
27/108 (25.0)
12/72 (16.7)
15/36 (41.7)
0.005
39 (1582)
37 (1279)
60 (19159)
0.37
Data are presented as n/N (%) or median (interquartile range), unless otherwise stated. LNZ: linezolid; XDR-TB: extensively drug-resistant TB.
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G. SOTGIU ET AL.
TUBERCULOSIS
0.14
(0.000.58)
ANGER [34]
0.33
(0.120.62)
DE LORENZO [35]
0.00
(0.000.71)
FORTN [22]
0.00
(0.000.60)
NAM [46]
0.36
(0.110.69)
MIGLIORI [8]
0.25
(0.010.81)
PARK [45]
0.57
(0.180.90)
SCHECTER [30]
0.13
(0.030.34)
SINGLA [31]
0.50
(0.230.77)
UDWADIA [32]
0.54
(0.250.81)
VILLAR [33]
0.78
(0.400.97)
0.00
(0.000.31)
VON DER
LIPPE [44]
0.2
0.4
0.6
0.8
FIGURE 2.
Forest plot showing the proportions of extensively drug-resistant tuberculosis (XDR-TB) patients in the enrolled studies. Data are presented as n (95% CI); I2:
TABLE 5
Treatment outcomes of 121 multidrug-resistant tuberculosis (TB) cases enrolled in the meta-analysis
All treatments
f600 mg
.600 mg
p-value
72 (59.5)
49 (40.5)
25/71 (35.2)
14/49 (28.6)
0.45
86/93 (92.5)
54/59 (91.5)
42/44 (95.5)
0.43
100/107 (93.5)
54/59 (91.5)
46/48 (95.8)
0.37
43.5 (2190)
45.5 (2891)
92.5 (35120)
0.02
37/72 (51.4)
18/42 (42.9)
19/30 (63.3)
0.09
61 (29119)
28 (2045)
60 (42115)
0.07
98/121 (81.0)
59/72 (81.9)
39/49 (79.6)
0.75
1/121 (0.8)
1/72 (1.4)
17/121 (14.1)
9/72 (12.5)
8/49 (16.3)
0.56
5/121 (4.1)
3/72 (4.2)
2/49 (4.1)
0.98
XDR-TB
Sputum smear conversion
Culture conversion
Data are presented as n (%), n/N (%) or median (interquartile range), unless otherwise stated. LNZ: linezolid; XDR-TB: extensively drug-resistant TB.
VOLUME 40 NUMBER 6
1435
TUBERCULOSIS
G. SOTGIU ET AL.
a)
ALFFENAAR [47]
1.00
(0.631.00)
ANGER [34]
1.00
(0.771.00)
DE LORENZO [35]
1.00
(0.291.00)
NAM [46]
0.82
(0.480.98)
MIGLIORI [8]
1.00
(0.401.00)
PARK [45]
1.00
(0.591.00)
SCHECTER [30]
0.96
(0.781.00)
SINGLA [31]
0.79
(0.490.95)
VILLAR [33]
0.89
(0.521.00)
1.00
(0.691.00)
VON DER
LIPPE [44]
0.2
0.4
0.6
0.8
b)
ALFFENAAR [47]
1.00
(0.631.00)
ANGER [34]
1.00
(0.771.00)
DE LORENZO [35]
1.00
(0.291.00)
FORTN [22]
1.00
(0.400.98)
NAM [46]
0.82
(0.480.98)
MIGLIORI [8]
1.00
(0.401.00)
PARK [45]
1.00
(0.591.00)
SCHECTER [30]
0.96
(0.781.00)
SINGLA [31]
0.79
(0.490.95)
VILLAR [33]
0.89
(0.521.00)
1.00
(0.691.00)
VON DER
LIPPE [44]
0.2
0.4
0.6
0.8
FIGURE 3.
Forest plots showing the proportion of a) sputum smear converters and b) culture converters in the enrolled studies. Data are presented as n (95% CI); I2:
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VOLUME 40 NUMBER 6
G. SOTGIU ET AL.
TUBERCULOSIS
1.00
ANGER [34]
0.73
(0.450.92)
DE LORENZO [35]
0.33
(0.010.91)
FORTN [22]
1.00
(0.401.00)
NAM [46]
0.64
(0.310.89)
MIGLIORI [8]
0.75
(0.190.99)
PARK [45]
0.71
(0.290.96)
SCHECTER [30]
0.96
(0.781.00)
SINGLA [31]
0.64
(0.350.87)
UDWADIA [32]
0.92
(0.641.00)
VILLAR [33]
0.89
(0.521.00)
0.90
(0.551.00)
VON DER
LIPPE [44]
(0.631.00)
0.2
0.4
0.6
0.8
FIGURE 4.
Forest plot showing the proportion of patients who were successfully treated in the enrolled studies. Data are presented as n (95% CI); I2: inconsistency
TABLE 6
Retrospective evaluation of the safety and tolerability of linezolid in 121 multidrug-resistant tuberculosis cases
Total
49 (40.5)
63/107 (58.9)
28/60 (46.7)
35/47 (74.5)
54/79 (68.4)
27/44 (61.4)
27/35 (77.1)
0.14
Anaemia
32/84 (38.1)
11/49 (22.5)
21/35 (60.0)
0.0005
0.012
Leukopoenia
p-value
0.004
7/85 (8.2)
1/50 (2.0)
6/35 (17.1)
Thrombocytopenia
10/85 (11.8)
5/50 (10.0)
5/35 (14.3)
0.55
Peripheral neuropathy
40/85 (47.1)
20/50 (40.0)
20/35 (57.1)
0.12
Optic neuritis
10/76 (13.2)
4/41 (9.8)
6/35 (17.1)
0.35
Gastro-intestinal disorders
14/84 (16.7)
4/50 (8.0)
10/34 (29.4)
0.01
300 (140690)
589.5 (154.5750)
252 (120540)
0.031
Data are presented as n/N (%) or median (interquartile range), unless otherwise stated. LNZ: linezolid.
VOLUME 40 NUMBER 6
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TUBERCULOSIS
G. SOTGIU ET AL.
a)
0.00
(0.001.37)
ANGER [34]
1.00
(0.781.00)
DE LORENZO [35]
0.67
(0.090.99)
FORTN [22]
1.00
(0.291.00)
NAM [46]
0.82
(0.480.98)
MIGLIORI [8]
1.00
(0.031.00)
PARK [45]
0.71
(0.290.96)
SCHECTER [30]
0.22
(0.070.44)
SINGLA [31]
0.71
(0.291.00)
UDWADIA [32]
1.00
(0.350.87)
VILLAR [33]
0.22
(0.030.60)
0.80
(0.440.97)
VON DER
LIPPE [44]
0.2
0.4
0.6
0.8
First author
[ref.]
Proportion of linezolid
interruption due to averse events
ALFFENAAR [47]
0.00
(0.000.37)
ANGER [34]
0.87
(0.600.98)
FORTN [22]
1.00
(0.291.00)
NAM [46]
0.82
(0.480.98)
MIGLIORI [8]
1.00
(0.031.00)
PARK [45]
0.40
(0.050.85)
SCHECTER [30]
1.00
(0.031.00)
SINGLA [31]
1.00
(0.691.00)
UDWADIA [32]
0.54
(0.250.81)
VILLAR [33]
1.00
(0.031.00)
0.70
(0.350.93)
VON DER
LIPPE [44]
0.2
0.4
0.6
0.8
FIGURE 5.
Forest plots showing a) the proportion of patients affected by adverse events and b) the proportion of patients who interrupted their treatment owing to
adverse events in the enrolled studies, respectively. Data are presented as n (95% CI); I2: inconsistency statistics; df: degrees of freedom.
VOLUME 40 NUMBER 6
G. SOTGIU ET AL.
TUBERCULOSIS
a)
ALFFENAAR [47]
0.00
(0.000.41)
ANGER [34]
0.67
(0.380.88)
DE LORENZO [35]
0.50
(0.010.99)
FORTN [22]
1.00
(0.291.00)
NAM [46]
0.18
(0.020.52)
MIGLIORI [8]
0.00
(0.000.98)
PARK [45]
0.14
(0.000.58)
SCHECTER [30]
0.20
(0.010.72)
SINGLA [31]
0.60
(0.260.88)
UDWADIA [32]
0.08
(0.000.36)
VILLAR [33]
0.50
(0.010.99)
0.75
(0.350.97)
VON DER
LIPPE [44]
0.2
0.4
0.6
0.8
Proportion of individuals
with peripheral neuropathy
ALFFENAAR [47]
0.00
ANGER [34]
0.40
(0.000.37)
(0.160.68)
DE LORENZO [35]
0.50
(0.010.99)
FORTN [22]
0.67
(0.090.99)
NAM [46]
0.73
(0.390.94)
MIGLIORI [8]
0.00
(0.000.98)
PARK [45]
0.57
(0.180.90)
SCHECTER [30]
0.60
(0.150.95)
SINGLA [31]
0.30
(0.070.65)
UDWADIA [32]
0.46
(0.190.75)
VILLAR [33]
0.50
(0.010.99)
0.75
(0.350.97)
0.2
0.4
0.6
0.8
FIGURE 6.
Forest plots showing a) the proportion of individuals affected by anaemia and b) the proportion of individuals affected by peripheral neuropathy in the
enrolled studies. Data are presented as n (95% CI); I2: inconsistency statistics; df: degrees of freedom.
c
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VOLUME 40 NUMBER 6
STATEMENT OF INTEREST
None declared.
ACKNOWLEDGEMENTS
The affiliation details for the authors are as follows: G. Sotgiu and P.
Castiglia: Epidemiology and Medical Statistics Unit, Dept of Biomedical
Sciences, University of Sassari, Sassari, Italy; R. Centis, L. DAmbrosio, E.
Zampogna and G.B. Migliori: World Health Organization Collaborating
Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care
and Research Institute, Tradate, Italy; J-W.C. Alffenaar: University of
Groningen, University Medical Center Groningen, Dept of Hospital and
Clinical Pharmacy, Groningen, the Netherlands; H.A. Anger: New York
City Dept of Health and Mental Hygiene, Bureau of Tuberculosis
Control, New York, NY, USA; J.A. Caminero: MDR-TB Unit, Dept of
Pneumology, University General Hospital of Gran Canaria Dr. Negrin,
Las Palmas de Gran Canaria, Spain and International Union against
Tuberculosis and Lung Disease (The Union), Paris, France; S. De
Lorenzo: AOVV E. Morelli Hospital, Reference Hospital for MDR and
HIV-TB, Sondalo, Italy; G. Ferrara: Lung Allergi Kliniken, Karolinska
University Hospital, Stockholm, Sweden, and Section of Respiratory
Diseases, Dept of Internal Medicine, University of Perugia, Terni, Italy;
W-J. Koh: Division of Pulmonary and Critical Care Medicine, Dept of
Medicine, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, Republic of Korea; G.F. Schecter: Tuberculosis
Control Branch, Division of Communicable Disease Control, Center for
Infectious Disease, California Dept of Public Health, Richmond, CA,
USA; T.S. Shim: Division of Pulmonary and Critical Care Medicine,
University of Ulsan College of Medicine, Asan Medical Center, Seoul,
Republic of Korea; R. Singla: Dept of Tuberculosis and Chest Diseases,
Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases,
New Delhi, India; A. Skrahina: Clinical Dept, National Research and
Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus;
A. Spanevello: Universita` degli Studi dellInsubria, Varese, and
Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy; Z.F.
EUROPEAN RESPIRATORY JOURNAL
G. SOTGIU ET AL.
TUBERCULOSIS
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